Rheumatoid synovial effuions (and other inflammatory joint fluids) are characterized by large numbers of T cells, many of which are activated, and another ill-defined population lacking cell surface receptors (E negative, Ig negative, Fc negative). Little is known about the functional significance of either population. There is evidence, however, for natural killer cell activity mediated by an Fc receptor negative NK cell. These characteristics are reminiscent of the results of the in vitro autologous mixed leukocyte reaction. We propose to analyze the following hypothesis; namely, in the rheumatoid joint B lymphocutes, transformed by an undefined stimulus, generate an autologous MLR. This leads to activation of T cells and the elaboration of factors that augment nonspecific cytotoxic activity. An additional consequence of this reaction would be the generation of large amounts of non-specific T cell-derived helper activity. This thesis would predict that n the rheumatoid joint one would find evidence of an increased or secondary type of autologous MLR, the presence of nonspecific cytotoxic cells lacking Fc receptors, and perhaps specific cytotoxic cells recognizing lymphocyte membrane defined antigen induced by the B cell transforming agent. The thesis is testable by comparing the autologous mixed leukocyte reaction in paired samples of peripheral blood and synovial fluid mononuclear cells. The hypothesis cannot explain why lymphocytes enter the articular cavity iitally, but it would account for the perpetuation of the inflammatory process. Therefore, experiments are included to demonstrate the presence of synovial fluid of mediators, particularly those related to the mast cell, capable of altering vascular permeability, and, in addition, to identify potentially important antigens, with particularl emphasis on the Epstein-Barr virus.